2. Cell Cycle/DNA Damage Apoptosis Epigenetics
  3. DNA/RNA Synthesis Apoptosis MDM-2/p53 Bcl-2 Family Caspase PARP
  4. NSC666715

NSC666715 is a DNA polymerase β (Pol-β) inhibitor. NSC666715 directly and specifically interacts with Pol-β, interferes with its binding to damaged DNA, blocks its dRP lyase activity, and inhibits Pol-β-mediated SN- and LP-BER. NSC666715 induces AP site accumulation and S-phase cell cycle arrest, and triggers senescence and apoptosis (apoptosis) via the p53/p21 pathway in colorectal cancer cells. NSC666715 enhances TMZ (HY-17364)-induced DNA damage, senescence and apoptosis, and potentiates the cytotoxicity of TMZ. NSC666715 inhibits tumor growth in colon cancer xenograft models. NSC666715 can be used in research related to colorectal cancer.

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NSC666715

NSC666715 Chemical Structure

CAS No. : 170747-33-8

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NSC666715 Related Antibodies

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RNASE L DNA Polymerases RNA Polymerases Helicases DNA Ligase

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Bcl-2 Bcl-xL Bcl-W Mcl-1 Bfl-1 Bcl-B Bax Bak Bim BNIP3 Bad

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Caspase 1 Caspase 2 Caspase 3 Caspase 4 Caspase 5 Caspase 6 Caspase 7 Caspase 8 Caspase 9 Caspase 10 Caspase 12 Caspase Caspase 11 Caspase-13

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PARP PARP1 PARP2 PARP3 PARP4 TNKS1/PARP5A TNKS2/PARP5B PARP7 PARP10 PARP14 PARP15 PARP12 PARP16

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Description

NSC666715 is a DNA polymerase β (Pol-β) inhibitor. NSC666715 directly and specifically interacts with Pol-β, interferes with its binding to damaged DNA, blocks its dRP lyase activity, and inhibits Pol-β-mediated SN- and LP-BER. NSC666715 induces AP site accumulation and S-phase cell cycle arrest, and triggers senescence and apoptosis (apoptosis) via the p53/p21 pathway in colorectal cancer cells. NSC666715 enhances TMZ (HY-17364)-induced DNA damage, senescence and apoptosis, and potentiates the cytotoxicity of TMZ. NSC666715 inhibits tumor growth in colon cancer xenograft models. NSC666715 can be used in research related to colorectal cancer[1][2].

IC50 & Target[1]

DNA Polymerase

 

Cellular Effect
Cell Line Type Value Description References
MCF7 IC50
7.4 μM
Compound: 11c
Antiproliferative activity against human MCF7 cells incubated for 72 hrs by MTT assay
Antiproliferative activity against human MCF7 cells incubated for 72 hrs by MTT assay
[PMID: 38516586]
MDA-MB-231 IC50
8.4 μM
Compound: 11c
Antiproliferative activity against human MDA-MB-231 cells incubated for 72 hrs by MTT assay
Antiproliferative activity against human MDA-MB-231 cells incubated for 72 hrs by MTT assay
[PMID: 38516586]
In Vitro

NSC666715 (0-50 μM; 45 min) potently inhibits Fen1-mediated Pol-β strand displacement activity and blocks the LP-BER pathway in an in vitro reconstitution system, with complete inhibition observed at a concentration of 50 μM[1].
NSC666715 (25 μM; 2 h) increases the apurinic/apyrimidinic (AP) site load in HCT116 cells, and when combined with 500 μM TMZ (HY-17364), it further enhances TMZ-induced AP site accumulation[1].
NSC666715 (50 μM; 48 h) increases p21 levels in HCT116 (p53+/+) cells; when combined with TMZ, it enhances the induced expression of p53 and p21[1].
Combination treatment with NSC666715 (50 μM; 2 h) and TMZ maintains S-phase arrest, which can be abrogated by PFTα (HY-15484)[1].
NSC666715 (10-100 μM; 2 h) enhances temozolomide (TMZ)-induced senescence in HCT116 cells, and this effect depends on the p53/p21 pathway[1].
NSC666715 (50 μM; 2 h) enhances the apoptotic signaling pathway induced by TMZ in HCT116 cells: when combined with TMZ, it downregulates the expression of the anti-apoptotic protein Bcl2, upregulates the expression of the pro-apoptotic protein Bax, activates caspase 3 and induces PARP1 cleavage via a caspase-dependent, AIF-independent pathway[1].
NSC666715 (5-15 μM) potently inhibits the strand displacement activity and 1-nt incorporation activity of purified human Pol-β[2].
NSC666715 dose-dependently inhibits the dRP lyase activity of purified human Pol-β, with an IC50 of 4.1 μM[2].
NSC666715 inhibits purified human Pol-β-mediated SN-BER in a dose-dependent manner, with an IC50 of 3.8 μM[2].
NSC666715 dose-dependently inhibits the LP-BER activity mediated by purified human Pol-β[2].
NSC666715 (10 μM) significantly reduces the ability of purified human Pol-β to bind gapped DNA[2].
NSC666715 (25-100 μM; 1 h pretreatment, followed by 48 h TMZ co-treatment) dose-dependently enhances the cytotoxicity of TMZ in mismatch repair-deficient HCT-116-APC (WT), HCT-116-APC (KD) and mismatch repair-proficient HCT-116+ch3 human colon cancer cells[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

NSC666715 Related Antibodies

Western Blot Analysis[1]

Cell Line: HCT116 (p53+/+) human colon cancer cells
Concentration: 50 μM (NSC666715); 500 μM (TMZ)
Incubation Time: 48 h
Result: Did not affect p53 levels but increased p21 levels when used alone.
Combination treatment with TMZ increased both p53 and p21 levels to a similar extent as their individual treatments.

Cell Cycle Analysis[1]

Cell Line: HCT116 human colon cancer cells
Concentration: 50 μM (NSC666715); 500 μM (TMZ); 10, 20, 30 μM (PFTα)
Incubation Time: 2 h (pretreatment); 48 h (TMZ treatment)
Result: Had no effect on cell cycle phase distribution when used alone, with 83% of cells in G0/G1, 11% in S phase, 6% in G2/M, and 2% in sub-G1 (apoptosis).
When combined with TMZ, the percentage of cells in S phase was 21% (with 10 μM PFTα), 20% (with 20 μM PFTα), and 21% (with 30 μM PFTα), which was reduced compared to TMZ alone.

Western Blot Analysis[1]

Cell Line: HCT116 human colon cancer cells
Concentration: 50 μM (NSC666715); 500 μM (TMZ); 10, 20, 30 μM (PFTα)
Incubation Time: 2 h (pretreatment); 48 h (TMZ treatment)
Result: Had no effect on Bcl2 or Bax levels when used alone.
Combined with TMZ, decreased Bcl2 levels and increased Bax levels.
Combination treatment also increased levels of cleaved caspase 3 and cleaved PARP1, while AIF levels remained unchanged.

Cell Cytotoxicity Assay[2]

Cell Line: MMR-deficient human colon cancer cell lines HCT-116-APC(WT) and HCT-116-APC(KD), MMR-proficient human colon cancer cell line HCT-116+ch3
Concentration: 25 μM, 50 μM, 100 μM
Incubation Time: 1 h pretreatment, followed by 48 h TMZ co-treatment
Result: Enhanced TMZ cytotoxicity in all three cell lines in a dose-dependent manner.
Reduced TMZ IC50 for HCT-116-APC(WT) from 312 μM to 156 μM (25 μM NSC666715), 107 μM (50 μM NSC666715), and 55 μM (100 μM NSC666715).
Reduced TMZ IC50 for HCT-116-APC(KD) from 491 μM to 205 μM (25 μM NSC666715), 178 μM (50 μM NSC666715), and 154 μM (100 μM NSC666715).
Reduced TMZ IC50 for HCT-116+ch3 from 128 μM to 100 μM (25 μM NSC666715) and 24 μM (50 μM NSC666715).
Showed very low cytotoxicity alone at concentrations up to 100 μM.
In Vivo

NSC666715 (10 mg/kg; i.p.; daily; 5 consecutive days) alone reduces colorectal xenograft tumor growth by 37-54% and, when combined with TMZ, reduces tumor growth by 62-71% in SCID mice, with the greatest efficacy in MMR-proficient tumors[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: SCID (female, 6-week-old, subcutaneous xenograft of HCT-116-APC(WT), HCT-116-APC(KD), or HCT-116+ch3 human colon cancer cells)[2]
Dosage: 10 mg/kg
Administration: i.p.; daily; 5 consecutive days
Result: Reduced xenograft tumor volume by 37% to 54% across all three cell lines.
Further reduced tumor growth by 62% to 71% when combined with temozolomide relative to vehicle control.
Showed no difference in body weight gain compared to vehicle controls.
Molecular Weight

430.33

Formula

C15H13Cl2N5O2S2
CAS No.
SMILES

O=S(C1=CC(C)=C(Cl)C=C1S)(NC2=NN=C(NC3=CC=C(Cl)C=C3)N2)=O
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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NSC666715 Related Classifications

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Help & FAQs
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    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

NSC666715170747-33-8NSC 666715NSC-666715DNA/RNA SynthesisApoptosisMDM-2/p53Bcl-2 FamilyCaspasePARPpoly ADP ribose polymerasep53/p21 pathwayLP-BERSCID miceSN-BERPol-βcolon cancer cellsHCT116 human colon cancer cellsDNA polymerase βcolorectal cancercolon cancer xenograft modelsInhibitorinhibitorinhibit

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